Coxsackievirus B3 (CVB3) infection causes myocarditis and dilated cardiomyopathy. The pathogenic mechanisms of the disease are complex. Myocarditis susceptibility correlates with activation of T cells expressing the Vgamma4 T cell receptor (TCR), CD4+ Thi (IFNgamma+) and CD8+alphabeta TCR+ autoimmune cytolytic T cells (CTL). Myocarditis resistance correlates to activation of Vgamma1+ and CD4+Th2 (IL4+) cells, and the absence of autoimmune CD8+alphabeta TCR+ effectors. Vgamma4+ cells kill both CVB3-infected myocytes and CD4+Th2 cells in vitro, and comprise up to 50% of the inflammatory T cells in the heart. CD8+alphabeta TCR+ autoimmune CTL kill uninfected but not virus-infected myocytes, and are the second most populous inflammatory cells in myocarditis. Since both Vgamma4+ and CD8+alphabeta TCR+ cells are cytolytic to cardiac myocytes in vitro, either or both populations might contribute to cardiac injury in vivo. Vgamma4+ cells recognize CD1, a major histocompatibility complex (MHC) class I-like molecule which normally presents hydrophobic lipid or peptide antigens. The autoimmune CD8+alphabeta TCR+ cells recognize antigen presented by classical MHC class I molecules. The overall goal of this application is to define the relative contributions of Vgamma4+ and CD8+alphabeta TCR+ cells to myocarditis in vivo, and determine whether Vgamma4+ cells facilitate CD8+alphabeta TCR+ cell activation by promoting CD4+ Th1 cell responses. The Specific Aims are to: 1) determine the relative importance of Vgamma4+ cell mediated killing of myocytes or modulation of CD4+ cell phenotype and activation of CD8+alphabeta TCR+ CTL in myocarditis; 2) determine CD1d expression in pathogenic versus non-pathogenic CVB3 infections and the role for lipid or peptide antigens in the CD1d-restricted Vgamma4+ T cell response; and 3) determine whether Vgamma4+ cells kill CD4+Th2 cells through CD1 -restricted responses.